The present invention is directed to substituted naphthothiazolium; aromatic guanylhydrazones, and other compounds and compositions with anti-malarial activity useful for the treatment and prophylaxis of malaria.
Malaria continues to be a major disease in most of the developing world. The estimated 300 million cases that occur per year result in considerable morbidity (e.g. fever, malaise, anorexia, anemia) and mortality of over 2 million children under the age of five (1). The intracellular protozoa, P. falciparum, accounts for greater than 95% of the malaria deaths. An important contributor to the increase in the incidence of malaria over the past 30 years has been the development of resistance of the malarial parasite to quinoline-containing anti-malarials such as chloroquine and quinine (2). In addition, it has been recognized that a number of complications, such as anemia, failure to gain weight and immunosuppression, associated with malaria infections continue to occur for weeks and even months after the parasites are cleared from the body (3,4,5).
The malaria pigment, hemozoin, is a unique polymer of heme molecules produced by the malaria parasite as a product of hemoglobin catabolism within the food vacuole (6) that serves to protect the parasite from potentially toxic free heme, as well as to induce pathology in the infected host. Over time, the intraerythrocytic parasite exhausts this energy and protein supply and then begins the next stage of its life cycle. Through a series of DNA and membrane divisions, each trophozoite will form 8-12 merozoites and one large xe2x80x9cgarbage bagxe2x80x9d containing polymerized hemozoin. When the infected red blood cell bursts, the merozoites go o to infect new cells and the hemozoin is released into the blood stream where it is scavenged by macrophages. The hemozoin is extremely stable and remains undegraded in the host organism for an extended period of time (years), mostly concentrated in the liver, kidneys and spleen.
Studies have demonstrated that hemozoin, either chemically made or isolated from the natural source, stimulates the production of tumor necrosis factor (TNF), and the macrophage inflammatory proteins, MIP-1xcex1 and MIP-1xcex2, in both murine macrophages and in human peripheral blood monocytes in vitro. This cytokine release is specific for hemozoin and not secondary to ingestion of particulate matter (e.g., latex beads), heme-containing compounds (hematin or hemin crystals) or to contamination with endotoxin (25). Administration of chemically synthesized hemozoin to rats provoked a dysregulation of temperature comparable to that observed with the administration of endogenous pyrogens, such as TNF and MIP-1xcex1.
In contrast to induction of cytokines by lipopolysaccharide (LPS) which peaks within hours and is promptly shut off, the indigestible hemozoin continues to induce TNF for 72 hours. This prolonged stimulation of cytokines is believed responsible for the elevated serum levels of TNF that are observed many weeks after malaria infections have been cured in children (28). The indigestible hemozoin continues to stimulate the macrophage to produce cytokines for long periods prolonging the time needed for recovery after resolution of the infection. Furthermore, macrophages laden with hemozoin have a number of impaired effector functions (7,8,9). These include decreased ability to mount an oxidative burst, decreased killing of pathogens, antigen presentation and a depression of cellular immunity.
Since plasmodia have evolved this unique mechanism to detoxify potentially toxic heme, interfering with its production would adversely effect the parasites since they have no mechanism to rid heme from the food vacuole. In contrast, mammals use heme oxygenase to break down heme to bilirubin. It has been proposed that the mechanism of action of quinoline containing drugs such as chloroquine and quinine was by interference with the heme polymerization process in the food vacuole of the parasite (26,27). This inhibition would lead to the accumulation of free heme which would be toxic to the parasite. The structure of hemozoin and the prevention of its formation by chloroquine has been confirmed by several workers (10,11,12).
It is towards the development of new antimalarial compounds which depolymerize hemozoin, both to kill parasites and reduce hemozoin toxicity in the host, that the present application is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as xe2x80x9cPrior Artxe2x80x9d to the instant application.
In accordance with the present invention,a method is provided for treating a mammal suffering from malaria or the sequelae of malarial infection comprising administering a therapeutically effective amount of a compound of the formula: 
wherein R1 is hydrogen, alkenyl, hydroxy(lower)alkyl, di[(lower)alkyl]amino(lower)alkyl, a heterocyclic, group, or a lower alkyl group optionally substituted by a heterocyclic group; R2 is cycloalkyl, alkenyl, lower alkyl, hydroxy(lower alkyl), di[hydroxy(lower)alkyl]amino(lower)alkyl, a heterocyclic group, or an aryl group optionally substituted by a 1-(guanylhydrazono)alkyl group; R3 is hydrogen or a 1-(guanylhydrazono)alkyl group; or a pharmaceutically acceptable salt therefor. R1 may be for example hydroxyethyl, allyl; dimethylaminopropyl, morpholinopropyl, or an ethyl group. R2 may be for example a cyclohexyl, allyl, phenyl, morpholinopropyl, methylpiperazinopropyl, di(hydroxyethyl)aminopropyl, ethyl, propyl, hydroxyethyl, or 3-[1-(guanylhydrazono)ethyl]phenyl group. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Preferred compounds include but are not limited to:
1-ethyl-2-(ethylimino)-1,2-dihydro-4-methylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-1,4-dimethyl-2-[[3-(4-methyl-1-piperazinyl)propyl]imino]naphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-[3-(dimethylamino)propyl]naphtho[1,2-d]thiazol-5-ol;
2-[[3-[1-[2-(aminoiminomethyl)hydrazono]ethyl]phenyl]amino]-4-methylnaphtho[1,2-d]thiazol-5-ol;
2-[[3-[bis(2-hydroxyethyl)amino]propyl]imino]-1,2-dihydro-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-4-methyl-1-(2-propenyl)-2-(2-propenylimino)naphtho[1,2-d]thiazol-5-ol;
4-methyl-2-(2-propenylamino)naphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-5-hydroxy-4-methylnaphtho[1,2-d]thiazole-1(2H)-ethanol;
1,2-dihydro-2-[(2-hydroxyethyl)imino]-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-1,4-dimethyl-2-(phenylimino)naphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-4-methyl-2-(phenylimino)naphtho[1,2-d]thiazol-5-ol;
4-methyl-2-[[3-(4-morpholino)propyl]amino]naphtho[1,2-d]thiazol-5-ol;
8-[1-[2-(aminoiminomethyl)hydrazono]ethyl]-2-(butylimino)-1,2-dihydro-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-[3-(4-morpholino)propyl]naphtho[1,2-d]thiazol-5-ol;
2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-[3-(4-methyl-1-piperazinyl)propyl]naphtho[1,2-d]thiazol-5-ol;
2-[[3-(dimethylamino)propyl]imino]-1,2-dihydro-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol;
1,2-dihydro-4-methyl-1-[3-(dimethylamino)propyl]-2-(1-methylethyl)aminonaphtho[1,2-d]thiazol-5-ol.
The present invention is also directed to a method for treating a mammal suffering from malaria or the sequelae of malaria infection comprising administering a therapeutically effective amount of a compound of the formula: 
wherein X and Y are independently N or CH, with the proviso that X and Y are not both N; R1 and R2 are both hydrogen or lower alkyl groups; wherein R3 and R4 are independently hydrogen, hydroxy, amino, lower alkoxy, lower alkyl or a 1-(guanylhydrazono)alkyl group; or a pharmaceutically acceptable salt thereof. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Preferred compounds include but are not limited to:
2,2xe2x80x2-[(4,6-dihydroxy-1,3-phenylene)diethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(4-hydroxy-1,3-phenylene)diethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-(1,3-phenylenediethylidyne)bis(hydrazinecarboximidamide);
2,2xe2x80x2[(2-hydroxy-5-methyl-1,3-phenylene)dimethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(2-methoxy-5-methyl-1,3-phenylene)dimethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(2-amino-1,3-phenylene)diethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(4-hydroxy-1,3-phenylene)dimethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-(1,3-phenylenedimethylidyne)bis(hydrazinecarboximidamide);
2,2xe2x80x2-(2,6-pyridinediyldiethylidyne)bis(hydrazinecarboximidamide);
2,2xe2x80x2-(3,5-pyridinediyldiethylidyne)bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(2,6-dimethyl-3,5-pyridinediyl)diethylidyne]bis(hydrazinecarboximidamide);
2,6-bis[1-[[(dimethylamino)acetyl]hydrazono]ethyl]pyridine;
2,2xe2x80x2-[(5-amino-1,3-phenylene)diethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(5-hydroxy-1,3-phenylene)diethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2,2xe2x80x3-(1,3,5-benzenetriyltriethylidyne)tris(hydrazinecarboximidamide); and
2,2xe2x80x2-(1,3-phenylenedipentylidyne)bis(hydrazinecarboximidamide).
The present invention is further directed to a method for treating a mammal suffering from malaria or the sequelae of malarial infection comprising administering a therapeutically effective amount of a compound of the formula: 
wherein Ar is an aromatic group and R1, R2, and R3 are independently selected from hydrogen, hydroxy, alkoxy, benzyloxy, N-methylthiourea, dialkylamino and an aminodimethylpyrimidinylamino group; wherein R4 is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof. Aryl may be, for example, a phenyl, naphthyl, 1,4-dihydro-1,4-dioxo-3-methyl-7-naphthalenyl, benzopyran-4-on-3-yl, quinolinyl or a benzopyrano[2,3-b]pyridine group. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Preferred compounds include but are not limited to:
2-[(2,3-dihydroxyphenyl)methylene]hydrazinecarboximidamide;
2-[(2-hydroxyphenyl)methylene]hydrazinecarboximidamide;
2-[(2-hydroxy-5-methoxyphenyl)methylene]hydrazinecarboximidamide;
2-[(2-hydroxy-1-naphthyl)methylidene]hydrazinecarboximidamide;
2-[(1-hydroxy-2-naphthyl)ethylidene]hydrazinecarboximidamide;
2-[(2-pyridyl)methylene]hydrazinecarboximidamide;
2-[(4-quinolinyl)methylene]hydrazinecarboximidamide;
2-[(3,4-dihydroxyphenyl)ethylidene]hydrazinecarboximidamide;
2-[(4-hydroxyphenyl)ethylidene]hydrazinecarboximidamide;
2-[(2-hydroxyphenyl)ethylidene]hydrazinecarboximidamide;
2-[(2-hydroxy-4-methoxyphenyl)methylene]hydrazinecarboximidamide;
2-{[2-hydroxy-4-(diethylamino)phenyl]methylene}hydrazinecarboximidamide;
2-[[3-(3,4-dimethyl-2(3H)-imino-6-pyrimidinyl)phenyl]ethylidene]hydrazinecarboximidamide;
2-[[4-(3,4-dimethyl-2(3H)-imino-6-pyrimidinyl)phenyl]ethylidene]hydrazinecarboximidamide;
2-[1-(4-benzyloxy-2-hydroxy-3-methylphenyl)ethylidene]hydrazinecarboximidamide;
2-amino-3-[(aminoiminomethyl)hydrazono]methyl]-6-chloro-4H-1-benzopyran-4-one;
2-[(1,4-dihydro-1,4-dioxo-3-methyl-7-naphthalenyl)ethylidene]hydrazinecarboximidamide;
2-[[1-[(aminoiminomethyl)hydrazono]-1,4-dihydro-3-methyl-4-oxo-7-naphthalenyl]ethylidene]hydrazinecarboximidamide;
N-[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]-Nxe2x80x2-methylthiourea;
2-[(2,3,4-trihydroxyphenyl)methylene]hydrazinecarboximidamide;
2-[(2,5-dihydroxyphenyl)methylene]hydrazinecarboximidamide;
2-[(4-hydroxy-3-methoxyphenyl)ethylidene]hydrazinecarboximidamide;
2-[(3,4-dihydroxy-5-methoxyphenyl)methylene]hydrazinecarboximidamide;
1-(2-hydroxyethyl)-2-[(2-pyridyl)methylene]hydrazinecarboximidamide;
2-[[2-hydroxy-4-(diethylamino)phenyl]methylene]hydrazinecarboximidamide; and
3-[1-[(aminoiminomethyl)hydrazono]ethyl]-2-methyl-5H-1-benzopyrano[2,3-b]pyridin-5-one.
The invention also provides for a method for treating a mammal suffering from malaria or the sequelae of malarial infection comprising administering a therapeutically effective amount of
2,2xe2x80x2-[(1,4-dihydro-1,4-dioxo-2,3-naphthalenediyl)bis(1-methyl-3-propanyl-1-ylidene)]bis(hydrazinecarboximidamide);
N,Nxe2x80x2-bis[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]pentanediamide;
2,6-bis[1-[[(dimethylamino)acetyl]hydrazono]ethyl]pyridine;
2-[3-(1,4-dihydro-1,4-dioxo-3-methyl-2-naphthalenyl)-1-methylpropylidene]hydrazinecarboximidamide;
1-[(aminoiminomethyl)hydrazono]-1,4-dihydro-3-methyl-4-oxonaphthalene;
2,2xe2x80x2-(1,4-cyclohexanediylidene)bis(hydrazinecarboximidamide);
N-[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]-Nxe2x80x2-methylthiourea;
or pharmaceutically acceptable salts thereof.
The present invention is further directed to a method for depolymerizing hemozoin in a mammal infected with malaria comprising administering to said mammal a hemozoin-depolymerizing effective amount of a compound of the formula 
wherein R1 is hydrogen, alkenyl, hydroxy(lower)alkyl, di[(lower)alkyl]amino(lower)alkyl, a heterocyclic group or a lower alkyl group optionally substituted by a heterocyclic group; R2 is cycloalkyl, alkenyl, lower alkyl, hydroxy(lower alkyl), di[hydroxy(lower)alkyl]amino(lower)alkyl, a heterocyclic group, or an aryl group optionally substituted by a 1-(guanylhydrazono)alkyl group; R3 is hydrogen or a 1-(guanylhydrazono)alkyl group; or a pharmaceutically acceptable salt therefor. R1 may be for example hydroxyethyl, allyl, dimethylaminopropyl, morpholinopropyl, or an ethyl group. R2 may be for example a cyclohexyl, allyl, phenyl, morpholinopropyl, methylpiperazinopropyl, di(hydroxyethyl)aminopropyl, ethyl, propyl, hydroxyethyl, or 3-[1-(guanylhydrazono)ethyl]phenyl group. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Non-limiting examples of substituents and preferred compounds are those as described hereinabove.
The present invention also provides for a method for depolymerizing hemozoin in a mammal infected with malaria comprising administering to said mammal a hemozoin-depolymerizing effective amount of a compound of the formula 
wherein X and Y are independently N or CH, with the proviso that X and Y are not both N; R1 and R2 are both hydrogen or lower alkyl groups; wherein R3 and R4 are independently hydrogen, hydroxy, amino, lower alkoxy, lower alkyl or 1-(guanylhydrazono)alkyl group; or a pharmaceutically acceptable salt thereof. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Examples of preferred compounds are those as described hereinabove.
A method for depolymerizing hemozoin in a mammal infected with malaria is also provided comprising administering to said mammal a hemozoin-depolymerizing effective amount of a compound of the formula 
wherein Ar is an aromatic group and R1, R2, and R3 are independently selected from hydrogen, hydroxy, alkoxy, benzyloxy, N-methylthiourea, dialkylamino and an aminodimethylpyrimidinylamino group; wherein R4 is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof. Aryl may be, for example, a phenyl, naphthyl, 1,4-dihydro-1,4-dioxo-3-methyl-7-naphthalenyl, benzopyran-4-on-3-yl, quinolinyl or a benzopyrano[2,3-b]pyridine group. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Non-limiting examples are those described hereinabove.
A method is also provided for depolymerizing hemozoin in a mammal infected with malaria comprising administering to said mammal a hemozoin-depolymerizing effective amount of
2,2xe2x80x2-[(1,4-dihydro-1,4-dioxo-2,3-naphthalenediyl)bis(1-methyl-3-propanyl-1-ylidene)]bis(hydrazinecarboximidamide);
N,Nxe2x80x2-bis[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]pentanediamide;
2,6-bis[1-[[(dimethylamino)acetyl]hydrazono]ethyl]pyridine;
2-[3-(1,4-dihydro-1,4-dioxo-3-methyl-2-naphthalenyl)-1-methylpropylidene]hydrazinecarboximidamide;
1-[(aminoiminomethyl)hydrazono]-1,4-dihydro-3-methyl-4-oxonaphthalene;
2,2xe2x80x2-(1,4-cyclohexanediylidene)bis(hydrazinecarboximidamide);
N-[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]-Nxe2x80x2-methylthiourea;
or pharmaceutically acceptable salts thereof.
A further object of the present invention is to provide a method for ameliorating the adverse effects of hemozoin on host cells comprising administering an effective hemozoin-depolymerizing amount of a compound of formula 
wherein R1 is hydrogen, alkenyl, hydroxy(lower)alkyl, di[(lower)alkyl]amino(lower)alkyl, a heterocyclic group or a lower alkyl group optionally substituted by a heterocyclic group; R2 is cycloalkyl, alkenyl, a lower alkyl group, a hydroxy(lower alkyl) group, a di[hydroxy(lower)alkyl]amino(lower)alkyl group, a heterocyclic group, or an aryl group optionally substituted by a 1-(guanylhydrazono)alkyl group; R3 is hydrogen or a 1-(guanylhydrazono)alkyl group; or a pharmaceutically acceptable salt therefor. R1 may be for example hydroxyethyl, allyl, dimethylaminopropyl, morpholinopropyl, or an ethyl group. R2 may be for example a cyclohexyl, allyl, phenyl, morpholinopropyl, methylpiperazinopropyl, di(hydroxyethyl)aminopropyl, ethyl, propyl, hydroxyethyl, or 3-[1-(guanylhydrazono)ethyl]phenyl group. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Non-limiting examples of substituents and preferred compounds are those as described hereinabove.
A further object of the present invention is to provide a method for ameliorating the adverse effects of hemozoin on host cells comprising administering an effective hemozoin-depolymerizing amount of a compound of formula 
wherein X and Y are independently N or CH, with the proviso that X and Y are not both N; R1 and R2 are both hydrogen or lower alkyl groups; wherein R3 and R4 are independently hydrogen, hydroxy, amino, lower alkoxy, lower alkyl or 1-(guanylhydrazono)alkyl group; or a pharmaceutically acceptable salt thereof. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Non-limiting examples of preferred compounds are those as described hereinabove.
A further object of the present invention is to provide a method for ameliorating the adverse effects of hemozoin on host cells comprising administering an effective hemozoin-depolymerizing amount of a compound of formula 
wherein Ar is an aromatic group and R1, R2, and R3 are independently selected from hydrogen, hydroxy, alkoxy, benzyloxy, N-methylthiourea, dialkylamino and an aminodimethylpyrimidinylamino group; wherein R4 is hydrogen or lower alkyl; or a, pharmaceutically acceptable salt thereof. Aryl maybe, for example, a phenyl, naphthyl, 1,4-dihydro-1,4-dioxo-3-methyl-7-naphthalenyl, benzopyran-4-on-3-yl, quinolinyl or a benzopyrano[2,3-b]pyridine group. Non-limiting examples of salts include hydrochloride, dihydrochloride, sulfate, hemisulfate, and dimethanesulfonate. Non-limiting examples of substituents and compounds are those described hereinabove.
A method is also provided for ameliorating the adverse effects of hemozoin on host cells comprising administering an effective hemozoin-depolymerizing amount of
2,2xe2x80x2-[(1,4-dihydro-1,4-dioxo-2,3-naphthalenediyl)bis(1-methyl-3-propanyl-1-ylidene)]bis(hydrazinecarboximidamide);
N,Nxe2x80x2-bis[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]pentanediamide;
2,6-bis[1-[[(dimethylamino)acetyl]hydrazono]ethyl]pyridine;
2-[3-(1,4-dihydro-1,4-dioxo-3-methyl-2-naphthalenyl)-1-methylpropylidene]hydrazinecarboximidamide;
1-[(aminoiminomethyl)hydrazono]-1,4-dihydro-3-methyl-4-oxonaphthalene;
2,2xe2x80x2-(1,4-cyclohexanediylidene)bis(hydrazinecarboximidamide);
N-[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]-Nxe2x80x2-methylthiourea;
or pharmaceutically acceptable salts thereof.
In addition, the present invention is directed to the following anti-malarial compounds or pharmaceutically acceptable salts thereof, and compositions comprising the following compounds:
2,2xe2x80x2-[(4-hydroxy-1,3-phenylene)diethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(2-hydroxy-5-methyl-1,3-phenylene)dimethylidyne]bis(hydrazinecarboximidamide);
2,2xe2x80x2-[(2-methoxy-5-methyl-1,3-phenylene)dimethylidyne]bis(hydrazinecarboximidamide);
N-[3-[1-[(aminoiminomethyl)hydrazono]ethyl]phenyl]-Nxe2x80x2-methylthiourea;
2,2xe2x80x2-[(4-hydroxy-1,3-phenylene)dimethylidyne]bis(hydrazinecarboximidamide);
2,6-bis[1-[[(dimethylamino)acetyl]hydrazono]ethyl]pyridine dihydrochloride;
2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-[3-(dimethylamino)propyl]naphtho[1,2-d]thiazol-5-ol;
2-[[3-[1-[2-(aminoiminomethyl)hydrazono]ethyl]phenyl]amino]-4-methylnaphtho[1,2-d]thiazol-5-ol;
2-[[3-(3,4-dimethyl-2(3H)-imino-6-pyrimidinyl)phenyl]ethylidene]hydrazinecarboximidamide;
2-[[4-(3,4-dimethyl-2(3H)-imino-6-pyrimidinyl)phenyl]ethylidene]hydrazinecarboximidamide;
2,2xe2x80x2-(1,3-phenylenediethylidyne)bis(N-hydroxyhydrazinecarboximidamide);
2-[1-(4-benzyloxy-2-hydroxy-3-methylphenyl)ethylidene]hydrazinecarboximidamide;
2-[[2-hydroxy-4-(diethylamino)phenyl]methylene]hydrazinecarboximidamide;
4-methyl-2-[[3-(4-morpholino)propyl]amino]naphtho[1,2-d]thiazol-5-ol; and
8-[1-[2-(aminoiminomethyl)hydrazono]ethyl]-2-(butylimino)-1,2-dihydro-1,4-dimethylnaphtho[1,2-d]thiazol-5-ol.
It is thus an object of the present invention to provide a method for treating a mammal suffering from malaria and treating the sequelae of malarial infection.
It is a further object of the present invention to provide a method for depolymerizing hemozoin in a mammal infected with malaria comprising administering to said mammal a hemozoin-depolymerizing effective amount of a compound of the present invention.
It is yet a further object of the present invention to provide a method for ameliorating the adverse effects of hemozoin on host cells comprising administering an effective hemozoin-depolymerizing amount of a compound the present invention.